tbuckley/cabot-search huggingface dataset:
Accuracy of Xpert Ultra for the diagnosis of paediatric tuberculosis in a low TB burden country: a prospective multicentre study
Authors: David Aguilera-Alonso, Gonzalo Solís-García, Antoni Noguera-Julian, Julián González-Martín, Angely Román Cobeña, Fernando Baquero-Artigao, Carlos Toro Rueda, Paula Rodríguez-Molino, Iván Bloise Sánchez, Teresa Vallmanya, Albert Bernet-Sánchez, Laura Minguell Domingo, Adriana Rubio, Jesús Saavedra-Lozano, María Jesús Ruiz-Serrano, Daniel Blázquez-Gamero, Paula López-Roa, David Gomez-Pastrana, María Dolores López Prieto, Eva María López Medina, Ana Gil-Brusola, Andrea Martín Nalda, Antonio Soriano-Arandes, Teresa Tórtola, Lola Falcon-Neyra, Verónica González Galán, Marc Tebruegge, Begoña Santiago-García
Journal: Thorax (2022)

Introduction Childhood pulmonary tuberculosis (TB) remains a diagnostic challenge. This study aimed to evaluate the performance of Xpert Ultra for the diagnosis of pulmonary TB in children in a low TB prevalence setting. Methods Prospective, multicentre, diagnostic accuracy study. Children with clinical or radiological suspicion of pulmonary TB were recruited at 11 paediatric units in Spain. Up to three gastric or sputum specimens were taken on 3 consecutive days, and analysed by Xpert MTB/RIF, Xpert Ultra and culture in parallel. Results 86 children were included (median age 4.9 years, IQR 2.0–10.0; 51.2% male). The final diagnosis was pulmonary TB in 75 patients (87.2%); 33 (44.0%) were microbiologically confirmed. A total of 219 specimens, comprising gastric aspirates (n=194; 88.6%) and sputum specimens (n=25; 11.4%), were analysed. Using culture as reference standard and comparing individual specimens, the sensitivity was 37.8% (14/37) for Xpert MTB/RIF and 81.1% (30/37) for Xpert Ultra (p&lt;0.001); specificity was 98.4% (179/182) and 93.4% (170/182), respectively (p=0.02). In the per-patient analysis, considering positive results on any specimen, the sensitivity was 42.9% (9/21) for Xpert MTB/RIF and 81.0% for Xpert Ultra (17/21, p=0.01); specificity was 96.9% (63/65) and 87.7% (57/65, p=0.07), respectively. Conclusions In children with pulmonary TB in a low burden setting, Xpert Ultra has significantly higher sensitivity than the previous generation of Xpert assay and only marginally lower specificity. Therefore, in children undergoing evaluation for suspected pulmonary TB, Xpert Ultra should be used in preference to Xpert MTB/RIF whenever possible.
Cancer in children born after frozen-thawed embryo transfer: A cohort study
Authors: Nona Sargisian, Birgitta Lannering, Max Petzold, Signe Opdahl, Mika Gissler, Anja Pinborg, Anna-Karina Aaris Henningsen, Aila Tiitinen, Liv Bente Romundstad, Anne Lærke Spangmose, Christina Bergh, Ulla-Britt Wennerholm
Journal: PLoS Medicine (2022)

The aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception.We performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.2%) and 7,772,474 children were born after spontaneous conception, representing all children born between the years 1994 to 2014 in Denmark, 1990 to 2014 in Finland, 1984 to 2015 in Norway, and 1985 to 2015 in Sweden. Rates for any cancer and specific cancer groups in children born after each conception method were determined by cross-linking national ART registry data with national cancer and health data registries and population registries. We used Cox proportional hazards models to estimate the risk of any cancer, with age as the time scale. After a mean follow-up of 9.9 and 12.5 years, the incidence rate (IR) of cancer before age 18 years was 19.3/100,000 person-years for children born after ART (329 cases) and 16.7/100,000 person-years for children born after spontaneous conception (16,184 cases). Adjusted hazard ratio (aHR) was 1.08, 95% confidence interval (CI) 0.96 to 1.21, p = 0.18. Adjustment was performed for sex, plurality, year of birth, country of birth, maternal age at birth, and parity. Children born after FET had a higher risk of cancer (48 cases; IR 30.1/100,000 person-years) compared to both fresh embryo transfer (IR 18.8/100,000 person-years), aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005, and spontaneous conception, aHR 1.65, 95% CI 1.24 to 2.19, p = 0.001. Adjustment either for macrosomia, birth weight, or major birth defects attenuated the association marginally. Higher risks of epithelial tumors and melanoma after any assisted reproductive method and of leukemia after FET were observed. The main limitation of this study is the small number of children with cancer in the FET group.Children born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. The results should be interpreted cautiously based on the small number of children with cancer, but the findings raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications.Trial registration number: ISRCTN 11780826.
Measurement and Validation of the Comprehensive Score for Financial Toxicity (COST) in a Population With Diabetes
Authors: Minal R. Patel, Guanghao Zhang, Michele Heisler, Peter X.K. Song, John D. Piette, Xu Shi, Hae Mi Choe, Alyssa Smith, Kenneth Resnicow
Journal: Diabetes Care (2022)

The Comprehensive Score for Financial Toxicity-Functional Assessment of Chronic Illness Therapy (COST-FACIT) is a validated instrument measuring financial distress among people with cancer. The reliability and construct validity of the 11-item COST-FACIT were examined in adults with diabetes and high A1C.We examined the factor structure (exploratory factor analysis), internal consistency reliability (Cronbach α), floor/ceiling effects, known-groups validity, and predictive validity among a sample of 600 adults with diabetes and high A1C.COST-FACIT demonstrated a two-factor structure with high internal consistency: general financial situation (7-items, α = 0.86) and impact of illness on financial situation (4-items, α = 0.73). The measure demonstrated a ceiling effect for 2% of participants and floor effects for 7%. Worse financial toxicity scores were observed among adults who were women, were below the poverty line, had government-sponsored health insurance, were middle-aged, were not in the workforce, and had less educational attainment (P < 0.01). Worse financial toxicity was observed for those engaging in cost coping behaviors, such as taking less or skipping medicines, delaying care, borrowing money, "maxing out" the limit on credit cards, and not paying bills (P < 0.01). In regression models for the full measure and its two factors, worse financial toxicity was correlated with higher A1C (P < 0.01), higher levels of diabetes distress (P < 0.01), more chronic conditions (P < 0.01), and more depressive symptoms (P < 0.01).Findings support both the reliability and validity of the COST-FACIT tool among adults with diabetes and high A1C levels. More research is needed to support the use of the COST-FACIT tool as a clinically relevant patient-centered instrument for diabetes care.
Productivity Loss and Medical Costs Associated With Type 2 Diabetes Among Employees Aged 18–64 Years With Large Employer-Sponsored Insurance
Authors: Joohyun Park, Elizabeth Bigman, Ping Zhang
Journal: Diabetes Care (2022)

OBJECTIVE To estimate productivity losses and costs and medical costs due to type 2 diabetes (T2D) among employees aged 18–64 years. RESEARCH DESIGN AND METHODS Using 2018–2019 MarketScan databases, we identified employees with T2D or no diabetes among those with records on workplace absences, short-term disability (STD), and long-term disability (LTD). We estimated per capita mean annual time loss attributable to T2D and its associated costs, calculated by multiplying time loss by average hourly wage. We estimated direct medical costs of T2D in total and by service type (inpatient, outpatient, and prescription drugs). We used two-part models (productivity losses and costs and inpatient and drug costs) and generalized linear models (total and outpatient costs) for overall and subgroup analyses by age and sex. All costs were in 2019 U.S. dollars. RESULTS Employees with T2D had 4.2 excess days lost (20.8 vs. 20.3 absences, 6.4 vs. 3.3 STD days, and 1.0 vs. 0.4 LTD days) than those without diabetes. Productivity costs were 13.3% ($680) higher and medical costs were double (total $11,354 vs. $5,101; outpatient $4,558 vs. $2,687, inpatient $3,085 vs. $1,349, prescription drugs $4,182 vs. $1,189) for employees with T2D. Employees aged 18–34 years had higher STD days and outpatient costs. Women had more absences and STD days and higher outpatient costs than men. CONCLUSIONS T2D contributes nearly $7,000 higher annual per capita costs, mostly due to excess medical costs. Our estimates may assist employers to assess potential financial gains from efforts to help workers prevent or better manage T2D.
Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy
Authors: Jing Deng, Aneel Paulus, Douglas D. Fang, Alak Manna, Guangfeng Wang, Hengbang Wang, Saijie Zhu, Jianyong Chen, Ping Min, Yan Yin, Navnita Dutta, Nabanita Halder, Gina Ciccio, John A. Copland, James Miller, Bing Han, Longchuan Bai, Liu Liu, Mi Wang, Donna McEachern, Sally Przybranowski, Chao-Yie Yang, Jeanne A. Stuckey, Depei Wu, Caixia Li, Jeremy Ryan, Anthony Letai, Sikander Ailawadhi, Dajun Yang, Shaomeng Wang, Asher Chanan-Khan, Yifan Zhai
Journal: Clinical Cancer Research (2022)

Development of B-cell lymphoma 2 (BCL-2)-specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein-protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575).Computational modeling was used to design "lead" compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax. The antitumor effects of lisaftoclax were also evaluated in several xenograft models.Lisaftoclax selectively binds BCL-2 (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo.These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2-selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.
Polygenic enrichment distinguishes disease associations of individual cells in single-cell RNA-seq data
Authors: Martin Jinye Zhang, Kangcheng Hou, Kushal K. Dey, Saori Sakaue, Karthik A. Jagadeesh, Kathryn Weinand, Aris Taychameekiatchai, Poorvi Rao, Angela Oliveira Pisco, James Zou, Bruce Wang, Michael Gandal, Soumya Raychaudhuri, Bogdan Pasaniuc, Alkes L. Price
Journal: Nature Genetics (2022)
Multiscale 3D genome organization underlies ILC2 ontogenesis and allergic airway inflammation
Authors: Michaël F. Michieletto, John J. Tello-Cajiao, Walter K. Mowel, Aditi Chandra, Sora Yoon, Leonel Joannas, Megan L. Clark, Monica T. Jimenez, Jasmine M. Wright, Patrick Lundgren, Adam Williams, Christoph A. Thaiss, Golnaz Vahedi, Jorge Henao-Mejia
Journal: Nature Immunology (2022)
Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse
Authors: Meng Nie, Na Chen, Huanhuan Pang, Tao Jiang, Wei Jiang, Panwen Tian, LiAng Yao, Yangzi Chen, Ralph J. DeBerardinis, Weimin Li, Qitao Yu, Caicun Zhou, Zeping Hu
Journal: Journal of Clinical Investigation (2022)

Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non–small cell lung cancer (NSCLC), it is now understood that drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found that the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, and demonstrated that treatment with EGFR-TKI heightened the expression of the rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or ACh signaling could predictably regulate the extent of DTP formation in vitro and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an FDA-approved drug, darifenacin, retarded tumor relapse in vivo. Mechanistically, upregulated ACh metabolism mediated drug tolerance in part through activating WNT signaling via ACh muscarinic receptor 3 (M3R). Importantly, we showed that aberrant ACh metabolism in patients with NSCLC played a potential role in predicting EGFR-TKI response rate and progression-free survival. Our study therefore defines a therapeutic strategy — targeting the ACh/M3R/WNT axis — for manipulating EGFR TKI drug tolerance in the treatment of NSCLC.
ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung
Authors: Ana Rita Nobre, Erica Dalla, Jihong Yang, Xin Huang, Lena Wullkopf, Emma Risson, Pedram Razghandi, Melisa Lopez Anton, Wei Zheng, Jose A. Seoane, Christina Curtis, Ephraim Kenigsberg, Jianlong Wang, Julio A. Aguirre-Ghiso
Journal: Nature Cancer (2022)
p53 Inhibits Bmi-1-driven Self-Renewal and Defines Salivary Gland Cancer Stemness
Authors: Christie Rodriguez-Ramirez, Zhaocheng Zhang, Kristy A. Warner, Alexandra E. Herzog, Andrea Mantesso, Zhixiong Zhang, Eusik Yoon, Shaomeng Wang, Max S. Wicha, Jacques E. Nör
Journal: Clinical Cancer Research (2022)

Mucoepidermoid carcinoma (MEC) is a poorly understood salivary gland malignancy with limited therapeutic options. Cancer stem cells (CSC) are considered drivers of cancer progression by mediating tumor recurrence and metastasis. We have shown that clinically relevant small molecule inhibitors of MDM2-p53 interaction activate p53 signaling and reduce the fraction of CSC in MEC. Here we examined the functional role of p53 in the plasticity and self-renewal of MEC CSC.Using gene silencing and therapeutic activation of p53, we analyzed the cell-cycle profiles and apoptosis levels of CSCs in MEC cell lines (UM-HMC-1, -3A, -3B) via flow cytometry and looked at the effects on survival/self-renewal of the CSCs through sphere assays. We evaluated the effect of p53 on tumor development (N = 51) and disease recurrence (N = 17) using in vivo subcutaneous and orthotopic murine models of MEC. Recurrence was followed for 250 days after tumor resection.Although p53 activation does not induce MEC CSC apoptosis, it reduces stemness properties such as self-renewal by regulating Bmi-1 expression and driving CSC towards differentiation. In contrast, downregulation of p53 causes expansion of the CSC population while promoting tumor growth. Remarkably, therapeutic activation of p53 prevented CSC-mediated tumor recurrence in preclinical trials.Collectively, these results demonstrate that p53 defines the stemness of MEC and suggest that therapeutic activation of p53 might have clinical utility in patients with salivary gland MEC.
A citywide experiment testing the impact of geographically targeted, high-pay-off vaccine lotteries
Authors: Katherine L. Milkman, Linnea Gandhi, Sean F. Ellis, Heather N. Graci, Dena M. Gromet, Rayyan S. Mobarak, Alison M. Buttenheim, Angela L. Duckworth, Devin Pope, Ala Stanford, Richard Thaler, Kevin G. Volpp
Journal: Nature Human Behaviour (2022)
Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers
Authors: Felipe Batalini, Doga C. Gulhan, Victor Mao, Antuan Tran, Madeline Polak, Niya Xiong, Nabihah Tayob, Nadine M. Tung, Eric P. Winer, Erica L. Mayer, Stian Knappskog, Per E. Lønning, Ursula A. Matulonis, Panagiotis A. Konstantinopoulos, David B. Solit, Helen Won, Hans P. Eikesdal, Peter J. Park, Gerburg M. Wulf
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing. Experimental Design: We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973). Results: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score. Conclusions: Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.
Immunomodulatory‐Photodynamic Nanostimulators for Invoking Pyroptosis to Augment Tumor Immunotherapy
Authors: Wei Qiu, Wen Su, Jiming Xu, Mengyun Liang, Xianbin Ma, Peng Xue, Yuejun Kang, Zhi‐Jun Sun, Zhigang Xu
Journal: Advanced Healthcare Materials (2022)

Abstract Cancer immunotherapy is restricted to immune resistance caused by immunosuppressive tumor microenvironment. Pyroptosis involved in antitumor immunotherapy as a new schedule is prospective to reverse immunosuppression. Herein, acidic tumor microenvironment (TME)‐evoked MRC nanoparticles (MRC NPs) co‐delivering immune agonist RGX‐104 and photosensitizer chlorine e6 (Ce6) are reported for pyroptosis‐mediated immunotherapy. RGX‐104 remodels TME by transcriptional activation of ApoE to regress myeloid‐derived suppressor cells' (MDSCs) activity, which neatly creates foreshadowing for intensifying pyroptosis. Considering Ce6‐triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory‐photodynamic MRC nanodrugs will implement an aforementioned two‐pronged strategy to enhance gasdermin E (GSDME)‐dependent pyroptosis. RNA‐seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX‐104 acting on LXR/ApoE axis and pyroptosis, where RGX‐104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC‐elicited pyroptosis in combination with anti‐PD‐1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on remarkable antitumor immunity. MRC may initiate a new window for immuno‐photo pyroptosis stimulators augmenting pyroptosis‐based immunotherapy.
Gut microbiota mediates the inhibition of lymphopoiesis in dietary-restricted mice by suppressing glycolysis
Authors: Si Tao, Yiting Wang, Chenghui Yu, Rongrong Qiu, Yanjun Jiang, Jie Jia, Zhendong Tao, Liu Zhang, Bing Zou, Duozhuang Tang
Journal: Gut Microbes (2022)

Dietary restriction (DR) is one of the most robust interventions shown to extend health-span and remains on the forefront of anti-aging intervention studies, though conflicting results have been shown on its effect on lifespan both in rodents and primates. The severe inhibitory effects on the lymphoid lineage by DR remains one of its major negative downsides which reduces its overall beneficial effects on organismal health. Yet, the underlying mechanism of how DR suppresses the lymphoid system remains to be explored. Here, we show that antibiotic ablation of gut microbiota significantly rescued the inhibition of lymphopoiesis by DR. Interestingly, glycolysis in lymphocytes was significantly down-regulated in DR mice and pharmacological inhibition of glycolysis reverted this rescue effect of lymphopoiesis in DR mice with ablated gut microbiota. Furthermore, DR remarkably reconstructed gut microbiota with a significant increase in butyrate-producing bacterial taxa and in expression of But, a key gene involved in butyrate synthesis. Moreover, supplemental butyrate feeding in AL mice suppressed glycolysis in lymphoid cells and mimicked the inhibition of lymphopoiesis in AL mice. Together, our study reveals that gut microbiota mediates the inhibition on lymphopoiesis via down-regulation of glycolysis under DR conditions, which is associated with increased butyrate-synthesis. Our study uncovered a candidate that could potentially be targeted for ameliorating the negative effects of DR on lymphopoiesis, and therefore may have important implications for the wider application of DR and promoting healthy aging.
Nanoradiosensitizer with good tissue penetration and enhances oral cancer radiotherapeutic effect
Authors: Di Jing, Nian Jiang, Fengyi Wang, Chunping Mao, Shujun Han, Pui Yan Ho, Wenwu Xiao, Yuanpei Li, Jian Jian Li, Lu Zhang, Kit S. Lam
Journal: Biomaterials (2022)